This project is a continuation of Project 1 A. Significant progress was made on each of the original aims of this project. Our goals related to improved presymptomatic diagnosis of individuals with inherited predispositions to cancer were essentially obtained and that aim has been retired. Our work related to early detection continued to show that somatic mutations can be sensitive and specific markers of neoplastic cells. Moreover, the development of a new technology called BEAMing, which allows hundred of thousands of individual PCRs to be performed in one tube, further improved our ability to detect somatic mutations. In total, our studies suggest that somatic mutations have the potential to significantly outperform conventional markers for early detection. Accordingly, our current proposal will focus on three aims related to the application of somatic mutations for the early detection of neoplasia. Aim #1 will focus on identification of somatic mutations in fecal DMAfor the early detection of colorectal cancers and adenomas. Specifically, we will develop and validate a Stool Mutation Test (SMT) capable of detecting clinically relevant adenomas and cancers with >70% and >90% sensitivity, respectively, and >99% specificity. Aim #2 will focus on identification of somatic mutations in plasma DMAfor the detection of colorectal cancers. The major goal of this aim is development and validation of a Plasma Mutation Test (PMT) capable of detecting early colorectal cancers (Dukes A and B) with >50% sensitivity and >99% specificity. Aim #3 will focus on identification of somatic mutations in plasma DMA for the early detection of pancreatic cancers. The goal of this aim is to develop and validate a PMT capable of detecting early pancreatic cancers (Stage I and II) with >50% sensitivity and >99% specificity. These studies will utilize samples from Cores 2 and 3 to translate discoveries made in former Projects 1A and 1B to patient care. We will provide tools for early screening of patients in Core 3 familial registries, help in the characterization of patients evaluated in Project 3A and aid development of new approaches by Projects 2B and 3B. The overall goal of the above studies is to provide clinically practical assays for early detection and management of colorectal and pancreatic cancers. From a public health prospective, such early detection strategies have the best chance of reducing the morbidity and mortality associated with colorectal and pancreatic cancers in the near term.